A number of experimental models of diabetes mellitus (DM) exist in mice. The non-obese diabetic strain (NOD/Lt) develops insulin-dependent DM with immunologic pancreatic beta cell destruction and insulinopenia inherited in a polygenic fashion. The Leprdb strain develops non-insulin dependent DM characterized by obesity and insulin resistance due to a single nucleotide substitution in the leptin receptor gene (Lepr). There is evidence that the renal functional and morphological changes occurring in both strains of diabetic mice parallel much of what is seen clinically in humans, including the development of albuminuria and glomerular matrix accumulation. A great deal of effort and technological advancements have allowed the continual identification and sequencing of expressed genes, some related to known gene families and some novel. For the most part, these gene sequences are in accessible data bases. To determine the relevance of these gene products in various circumstances, he technique of massively parallel DNA analysis is being developed by a number of groups. This approach allows the determination of which genes are expressed in a given tissue at a particular time. In these studies, groups of NOD/Lt and Leprdb mice will be followed longitudinally. At different times, selected animals will be sacrificed for detailed evaluation of renal pathological changes relevant to human diabetic nephropathy. The expression of mRNA for genes potentially altered in Dm will be determined. Genes chosen based on logic detailed in the application will be evaluated using the technique of massively parallel DNA analysis. mRNA from diabetic and control glomeruli will be differentially labeled and hybridized with cDNA-containing microchips. A relative increase or decrease in the expression of these genes will be determined. The strategy will permit identification of known and novel genes that may be affected in experimental insulin- and noninsulin- dependent DM and correlate these with renal functional and pathological changes. Furthermore, successful completion of these pilot studies will justify additional work to: 1) identify analogous genes potentially altered in human diabetic nephropathy; 2) determine the importance of identified gene products in experimental diabetic nephropathy; and, 3) study additional genes and organ systems affected in DM.